Increased purine metabolism in the human diabetic retina implicates monosodium urate (MSU)-mediated inflammatory effects in diabetic retinopathy

Abstract

Purpose: Recent evidence suggests that uric acid (UA) in its crystal salt form of monosodium urate (MSU) has pro-inflammatory properties. Indeed, moderate hyperuricemia has been shown to be a potential risk factor for progression of cardiovascular disease, metabolic syndrome and diabetic nephropathy. Whether or not MSU is involved in DR pathogenesis is presently unclear. Here we have determined UA/MSU content in freshly isolated vitrei from diabetic and not diabetic patients undergoing vitrectomy in pars plana. In addition, we have analyzed the effects of hyperglycemia on purine metabolism in the human diabetic retina of post mortem donors and in vitreous of diabetic patients by analyzing the expression levels of xanthine oxidase (XOD) and purine nucleoside phosphorylase (PNPase).

Methods: Human retinal and vitreal samples were obtained from post-mortem diabetic donors by Georgia Eye Bank. Vitrei were also obtained from diabetic and not diabetic patients that underwent vitrectomy in pars plana. Diluted and undiluted vitreal samples were analyzed for UA levels using a colorimetric assay. The obtained values were then normalized according to total volume and protein content. Mass spectrometry, immunohistochemistry and Western analyses were used to identify XOD and PNPase.

Results: Measurements of UA in post-mortem and not post-mortem vitrei showed that UA concentration in diabetic samples was significantly increased in comparison to not diabetic samples. In addition UA levels in diabetic samples were higher than the nucleation threshold (6mg/dL), thus, suggesting that the levels measured corresponded for over 98% to MSU. In addition, we have found that expression levels of XOD and PNPase were significantly elevated in the diabetic post-mortem retinas and, interestingly, PNPase was also found in the vitreous of diabetic patients.

Conclusions: The results obtained in the present studies revealed increased purine metabolism in the diabetic retina that may lead to enhanced production of MSU and MSU-mediated inflammatory activities in the diabetic retina.

Keywords: 499 diabetic retinopathy • 557 inflammation